The purpose of the present proposal is to conduct basic research on the neurobiology and pharmacology of the central noradrenergic system, a brain system thought to play an important role in central responses to stress and in mechanisms of antidepressant drug action. Research on the behavioral functions of this system has been hampered by the lack of a suitable means to study the activity of its receptors in the brains of conscious, freely moving animals. Recent studies in our laboratory however have indicated that a new technique involving the detection by implanted microdialysis probes of increases in the level of the second messenger, cyclic AMP (cAMP), in the brain in vivo in response to infusion of catecholamines now makes possible the study of these receptors in the intact brain. The purpose of the proposed research is to further develop this technique and to use it to study the in vivo regulation of central noradrenergic receptor function by pharmacological processes which are related to various aspects of stress and depression. The first aim of the project is to determine the sensitivity of the microdialysis-cAMP method in detecting experimental alterations in brain receptor function and in detecting ongoing neurotransmission at these receptors. This will be accomplished a) by determining if the technique can detect the chronic desensitization and sensitization of cAMP responses to catecholamines caused by chronic administration of an antidepressant drug or a central noradrenergic lesion, and b) by determining if it can detect cAMP responses to endogenous norepinephrine released by various procedures including stress, amphetamine infusion and stimulation of the locus coeruleus. The second aim of the project is to utilize the microdialysis method to investigate physiological factors that modulate the output of noradrenergic receptors in vivo. The studies will focus on the adrenocortical system, a system known to be active during stress and thought to have regulatory effects on noradrenergic receptors and will determine if corticosterone alters the action of catecholamines on these receptors or protects them from desensitization during prolonged catecholamine exposure. The above research therefore has the potential for providing a new tool that will facilitate investigations of the role of the noradrenergic system in stress and antidepressant drug actions and of providing insight into the physiological regulation of noradrenergic receptors during stress and during psychopathological conditions in which the level of adrenocortical function is increased (e.g., endogenous depression).